Patients suffering from dementia with Lewy body (DLB) often see complex visual hallucinations (CVH). Despite many pathological, clinical, and neuroimaging studies, the mechanism of CVH remains unknown. One possible scenario is that top-down information is being used to compensate for the lack of bottom-up information. To investigate this possibility and understand the underlying mathematical structure of the CVH mechanism, we propose a simple computational model of synaptic plasticity with particular focus on the effect of selective damage to the bottom-up network on self-reorganization. We show neurons that undergo a change in activity from a bottom-up to a top-down network framework during the reorganization process, which can be understood in terms of state transitions. Assuming that the pre-reorganization representation of this neuron remains after reorganization, it is possible to interpret neural response induced by top-down information as the sensation of bottom-up information. This situation might correspond to a hallucinatory situation in DLB patients. Our results agree with existing experimental evidence and provide new insights into data that have hitherto not been experimentally validated on patients with DLB. https://www.selleckchem.com/products/bay-61-3606.html Previous studies have shown that during comprehension readers activate words beyond the unfolding sentence. An open question concerns the mechanisms underlying this behavior. One proposal is that readers mentally simulate the described event and activate related words that might be referred to as the discourse further unfolds. Another proposal is that activation between words spreads in an automatic, associative fashion. The empirical support for these proposals is mixed. Therefore, theoretical accounts differ with regard to how much weight they place on the contributions of these sources to sentence comprehension. In the present study, we attempted to assess the contributions of event simulation and lexical associations to discourse reading, using event-related brain potentials (ERPs). Participants read target words, which were preceded by associatively related words either appearing in a coherent discourse event (Experiment 1) or in sentences that did not form a coherent discourse event (Experiment 2). Contextually unexpected target words that were associatively related to the described events elicited a reduced N400 amplitude compared to contextually unexpected target words that were unrelated to the events (Experiment 1). In Experiment 2, a similar but reduced effect was observed. These findings support the notion that during discourse reading event simulation and simple word associations jointly contribute to language comprehension by activating words that are beyond contextually congruent sentence continuations. Tachykinin signaling system is present in both vertebrates and invertebrates, and functions as neuromodulator responsible for the regulation of various physiological processes. In human, the internalization of G protein-coupled receptors has been extensively characterized; however, the insect GPCR internalization has been rarely investigated. Here, we constructed two expression vectors of Bombyx tachykinin-related peptide receptor (BmTKRPR) fused with Enhanced Green Fluorescent Protein (EGFP) at the C-terminal end for direct visualization of receptor expression, localization, and trafficking in cultured mammalian HEK293 and insect Sf21 cells. Our results demonstrated that agonist-activated BmTKRPR underwent rapid internalization in a dose-and time-dependent manner via a clathrin-dependent pathway in both HEK293 and Sf21 cells. Further investigation via RNAi or specific inhibitors, or co-immunoprecipitation demonstrated that agonist-induced BmTKRPR internalization was mediated by PKC, GRK5 and β-arrestin2/BmKurtz. In addition, we also observed that most of the internalized BmTKRP receptors were recycled to the cell surface via early endosomes upon peptide ligand removal. Our study provides the first in-depth information on mechanisms underlying insect TKRP receptor internalization and perhaps aids in the interpretation of the signaling in the regulation of physiological processes. BACKGROUND AND AIMS Roux-en-Y gastric bypass (RYGB) is refractory to lifestyle and pharmacotherapy measures requiring reversal of the patient's bariatric surgery. Reversal can lead to weight re-gain and recrudescence of their comorbidities. Our aim was to report a multicenter experience on the endoscopic management of refractory dumping syndrome with endoscopic transoral outlet revision (TORe). METHODS A multicenter international series of consecutive patients who underwent TORe with a full-thickness endoscopic suturing device was analyzed for technical success, improvement in Sigstad scores, and weight trajectories after the procedure. Failure was defined as needing an enteral feeding tube, surgical reversal, or repeat TORe. RESULTS A total of 115 patients across 2 large academic centers in Germany and the United States underwent TORe for dumping syndrome. Patients were a mean 8.9±1.1 years from their initial RYGB with an average percent total body weight loss of 31%±10.6% (TBWL) at the time of endoscopy. Three months post-procedure, Sigstad score improved from a mean of 17±6.1 to 2.6±1.9 (paired t-test p=0.0001) with only 2% (n=2) patients experiencing weight gain. Mean weight loss (kg) and %TBWL 3 months post-TORe were 9.47 kg±3.6 and 9.47%±2.5, respectively. Six (5%) patients failed initial endoscopic therapy, with 50% (n=3) successfully treated with a repeat TORe. Three patients underwent surgical reversal indicating an overall 97% endoscopic success rate. CONCLUSION TORe as an adjunct to lifestyle and pharmacological therapy for refractory dumping syndrome is safe and effective at improving dumping syndrome and reducing rates of surgical revision. Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord.